For neuroblastoma are using four cell lines, two MYCN not-amplified and two MYCN amplified cell line that can be grown in a xenograft model. For RMS we will use at least four cell lines, tow with PAX3-FOXO1 fusion genes and two with RAS pathway mutated genes. Among other assays we will use the Incutyte system. For the siRNA screen we will use a druggable genome library of over 6000 genes developed by National Center for Advancing Translational Sciences (NCATS). For the drug screen we will use single agent and combination responses of a panel of 1916 drugs (Mechanism Interrogation Plate (MIPE-v4) Library) also developed by NCATS. The content of this library include 765 FDA approved compounds, 49 of which are approved for cancer therapy, 460 in clinical trials (phase 1, 2 or 3), 149 kinase inhibitors. For 1915 of these compounds, the target or mechanism of action is known. The most promising targets and the appropriate siRNA or drug combination will be further evaluated in the xenograft animal models as outlined above. All positive hits will be further screened in a wider panel of NB and RMS Xenografts which will be part of a panel of the Pediatric Preclinical Testing Program (PPTP) which is currently being utilized as a pipeline to screen new drugs and make recommendation for human pediatric phase 1/2 trials (http://ctep.cancer.gov/resources/child.html.)